Subarachnoid hemorrhage occurs generally in fourty- to sixtysomething virile aged persons, and refers to the condition that there is hemorrhage in the space between the brain-circumscribing arachnoid and the brain mainly as a result of aneurysm rupture. The intracranial pressure is instantaneously elevated by such a hemorrhage, to give damage to the brain. About 10% of the patients suffering from a subarachnoid hemorrhage will die immediately after the onset and about 25% will become serious, according to the statistics. Even if a patient suffering from a subarachnoid hemorrhage for the first time stays alive, re-hemorrhage is said to occur within 2 weeks in about 25% of the patient. The treatments of the subarachnoid hemorrhage include removal of hematoma and prevention of re-rupture of the ruptured aneurysm.
Subarachnoid hemorrhage itself is thus a very dreadful disease. Further, even after the treatment for subarachnoid hemorrhage, more than half of the patients may suffer from a peculiar pathological state, which is called cerebral vasospasm. Cerebral vasospasm is a reversible constriction of the cerebral main artery, which occurs in 3 to 14 days after subarachnoid hemorrhage and persists for 1 to 2 weeks. Cerebral ischemia as a result of the condition causes death in about 40% of the patients and serious sequelae in about 30%, and only about 30% can return to normal life. Accordingly, cerebral vasospasm is causing a serious problem.
In such a circumstance, however, researches concerning cerebral vasospasm have not been sufficiently promoted and neither prevention nor treatment of the disease has been established. For example, the mechanism of the development of subarachnoid hemorrhage to cerebral vasospasm remains unknown, though multiple factors including free radicals, lipid peroxidation, an arachidonate cascade, damages in the perivascular nerve, damages in endothelium-dependent relaxation, and structural change of the vascular wall have been suggested to be involved in a complicated manner. Therefore, prevention or treatment of cerebral vasospasm would be difficult if only one of these factors could be inhibited.
Fasudil hydrochloride or sodium ozagrel is currently administered as the systemic chemotherapy for cerebral vasospasm. The cisternal administration of a tissue plasminogen activator during operation for subarachnoid hemorrhage is also employed. The effect of these therapies, however, has been insufficient.
HMGB1 is a protein present in rodents to human beings, and 95% or more of the amino acid sequence thereof is common. HMGB1 exists in normal cells, and the blood level is increased by stimulation with an LPS: lipopolysaccharide which is a bacterial endotoxin released in sepsis: systemic inflammatory response syndrome, to produce tissue damage eventually. Accordingly, the method described in JP 2003-520763 T employs administration of an HMGB1 antagonist for the treatment of the symptoms by an activated inflammatory cytokine cascade. However, there is neither description nor suggestion concerning cerebral vasospasm in JP 2003-520763 T, although there is a description of many diseases and symptoms mediated by the inflammatory cytokine cascade as examples of the target diseases to be treated.
In addition, JP 2005-537253 T discloses a composition containing an HMGB1 antibody or the like for the treatment of side-effects induced by a necrotic tissue. The side effects are exemplified only by activation of viable cells in the vicinity, mobilization and activation of myelocytes, loss of barrier function of the endothelium, and edema; and there is no description or suggestion concerning cerebral vasospasm.